Cabazitaxel is a semi-synthetic taxane of the formula (I).

It is commercially available as an intravenous injection for the treatment of certain cancers (JEVTANA®, Sanofi-Aventis U.S. LLC). Several patents describe its composition and use. See, e.g., U.S. Pat. Nos. 5,438,072; 5,698,582; 5,847,170; 6,331,635; 6,372,780; 6,387,946; and 7,241,907. The U.S. Food and Drug Administration (FDA) approved the use of cabazitaxel in combination with prednisone for the treatment of metastatic hormone-refractory prostate cancer in 2010. Therapy employing cabazitaxel has been associated with a number of adverse reactions such as neutropenia, febrile neutropenia, severe hypersensitivity, gastrointestinal symptoms, renal failure, and hepatic impairment. Therefore, there is a need for improved cabazitaxel compositions to mitigate these adverse effects.
Platinum-containing drugs are used in some cancer therapies. Examples of such platinum drugs are cisplatin, carboplatin, and oxaliplatin, which are used clinically in the United States and elsewhere. The use of platinum(II) drugs in the treatment of malignancies has been somewhat limited because of the side effects and resistance acquired by cancer cells. An alternative to platinum(II) drug candidates is the use of substitutionally more inert platinum(IV) compounds as prodrugs derived from clinically effective platinum(II) compounds. Substitutionally inert platinum(IV) complexes are less likely to be deactivated prior to reaching their destination target in the cancer cell. The activity of platinum(IV) complexes generally involves reduction with concomitant loss of the axial ligands, affording an active platinum(II) complex that readily binds to DNA. The axial ligands that are released from the platinum(IV) complex may comprise a therapeutically active agent.
Some developments in nanomedicine are directed towards improving the pharmaceutical properties of drugs and creating or enhancing their targeted delivery in a cell-specific manner. Several cell-specific drugs are reported in literature, and include monoclonal antibodies, aptamers, peptides, and small molecules. Despite some potential advantages of these drugs, disadvantages have limited their clinical application. Such disadvantages include size, stability, manufacturing cost, immunogenicity, poor pharmacokinetics and other factors.
Nanoparticulate drug delivery systems are attractive for systemic drug delivery because of their potential to prolong drug circulation half-life, reduce non-specific uptake, and better accumulate at the tumors through an enhanced permeation and retention (EPR) effect. Several therapeutic nanoparticles such as Doxil® and Abraxane® are used as the frontline therapies.
The development of nanotechnologies for effective delivery of drugs or drug candidates to specific diseased cells and tissues, e.g., to cancer cells, in specific organs or tissues, in a tempospatially regulated manner can potentially overcome the therapeutic challenges faced to date. Accordingly, there is a need in the art for improved drug targeted conjugates utilizing targeting ligands with therapeutically active agents. It would be beneficial to link the therapeutic active drug to a platinum(IV) precursor and encapsulate this formulation in a nanoparticle.